Avaliação da síntese intratecal de imunoglobulinas no transplante de medula óssea

Almeida, Sérgio Monteiro de; Livramento, José Antonio; Pasqüini, Ricardo; Palou, Viviana Boccardi; Oliveira, Aparecido Mendes de; Doi, Elvira Missako; Ono, Margaret; Aso, Mirna Cigemi; Ferreira, Eurípides

doi:10.1590/S0004-282X1997000500018

Resumos

O envolvimento da doença do enxerto contra o hospedeiro crônica (DECH-C) no sistema nervoso central tem sido especulado. Há uma série de semelhanças clínicas e fisiopatológicas entre DECH-C e doenças auto-imunes, o que leva a questionar sobre a síntese intratecal de imunoglobulinas. Este estudo avalia esta síntese, em particular durante a DECH-C, de forma quantitativa e qualitativa, a fim de observar sua incidência e possível fisiopatologia. Foram estudadas amostras pareadas de LCR e soro de 33 pacientes com leucemia mielóide crônica submetidos a transplante de medula óssea (TMO) alogênico, com doador aparentado, HLA idêntico. As amostras foram coletadas nos períodos pré TMO, pós TMO e concomitante à DECH-C. Não foi evidenciada produção intratecal de IgG ou IgA nas várias fases do TMO. Apenas casos isolados evidenciaram síntese, inclusive de IgM, durante a DECH-C.

doença do enxerto contra o hospedeiro; barreira hemato-encefálica; auto-imunidade; imunoglobulinas; líquido cefalorraquidiano; transplante de medula óssea

The central nervous system involvement in chronic graft versus host disease (GVHD) has been suggested. Chronic GVHD resembles auto immune connective tissue disorders. In order to investigate the immunoglobulin intra blood brain barrier (BBB) synthesis during chronic GVHD, and contribute to understanding the pathophysiology of the disease, we studied 33 patients who underwent allogeneic bone marrow transplants (BMT) from HLA identical related donors. Immunoglobulin intra BBB synthesis was investigated quantitative and qualitatively. The samples were collected pre BMT, pos BMT and during chronic GVHD. There were no evidence of immunoglobulin intra BBB synthesis, and no oligoclonal bands were found. Only isolated cases suggested IgG and IgA intra BBB synthesis, and in one case IgM during GVHD.

graft-versus-host disease; blood-brain barrier; auto immunity; immunoglobulins; cerebrospinal fluid; bone marrow transplantation

Avaliação da síntese intratecal de imunoglobulinas no transplante de medula óssea

Immunoglobulins intrathecal synthesis evaluation in bone marrow transplantation

Sérgio Monteiro de Almeida^I; José Antonio Livramento^I; Ricardo Pasqüini^II; Viviana Boccardi Palou^III; Aparecido Mendes de Oliveira^IV; Elvira Missako Doi^V; Margaret Ono^V; Mirna Cigemi Aso^V; Eurípides Ferreira^VI

^INeurologista

^IIProfessor Titular, Disciplina de Hematologia

^IIIBiologista

^IVBiomédico

^VBioquímica

^VIProfessor Adjunto, Disciplina de Imunologia

RESUMO

O envolvimento da doença do enxerto contra o hospedeiro crônica (DECH-C) no sistema nervoso central tem sido especulado. Há uma série de semelhanças clínicas e fisiopatológicas entre DECH-C e doenças auto-imunes, o que leva a questionar sobre a síntese intratecal de imunoglobulinas. Este estudo avalia esta síntese, em particular durante a DECH-C, de forma quantitativa e qualitativa, a fim de observar sua incidência e possível fisiopatologia. Foram estudadas amostras pareadas de LCR e soro de 33 pacientes com leucemia mielóide crônica submetidos a transplante de medula óssea (TMO) alogênico, com doador aparentado, HLA idêntico. As amostras foram coletadas nos períodos pré TMO, pós TMO e concomitante à DECH-C. Não foi evidenciada produção intratecal de IgG ou IgA nas várias fases do TMO. Apenas casos isolados evidenciaram síntese, inclusive de IgM, durante a DECH-C.

Palavras-chave: doença do enxerto contra o hospedeiro, barreira hemato-encefálica, auto-imunidade, imunoglobulinas, líquido cefalorraquidiano, transplante de medula óssea.

ABSTRACT

The central nervous system involvement in chronic graft versus host disease (GVHD) has been suggested. Chronic GVHD resembles auto immune connective tissue disorders. In order to investigate the immunoglobulin intra blood brain barrier (BBB) synthesis during chronic GVHD, and contribute to understanding the pathophysiology of the disease, we studied 33 patients who underwent allogeneic bone marrow transplants (BMT) from HLA identical related donors. Immunoglobulin intra BBB synthesis was investigated quantitative and qualitatively. The samples were collected pre BMT, pos BMT and during chronic GVHD. There were no evidence of immunoglobulin intra BBB synthesis, and no oligoclonal bands were found. Only isolated cases suggested IgG and IgA intra BBB synthesis, and in one case IgM during GVHD.

Key words: graft-versus-host disease, blood-brain barrier, auto immunity, immunoglobulins, cerebrospinal fluid, bone marrow transplantation.

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Full text available only in PDF format.

Agradecimento - Ao Prof. Dr. Lineu César Werneck.

Aceite: 20-agosto-1997.

Projeto realizado com apoio da FAPESP (932705-6) e CAPES.

Estudo realizado na disciplina de Neurologia e Serviço de TMO do Hospital de Clínicas da Universidade Federal do Paraná (HC-UFPR), Disciplina de Imunologia da Escola Paulista de Medicina - Universidade Federal de São Paulo (EPM-UNIFESP) e Centro de Investigações em Neurologia da Faculdade de Medicina da Universidade de São Paulo (FMUSP).

Dr. Sérgio Monteiro de Almeida - Especialidade de Neurologia, Hospital de Clínicas UFPR- Rua General Carneiro 181, sala 1238 - 80060-900 Curitiba PR - Brasil.

1. Anderton B, Thorpe RC. New methods of analyzing for antigens and glycoproteins in complex mixtures. Immunol Today 1980;1:122-127.
2. Barker CF, Billingham RE. Immunologically privileged sites. Adv Immunol 1977;25:1-8.
3. Barrett AJ. Graft versus host diseasexlinical features and biology. Bone Marrow Transpl 1989;4(Suppl 4): 18-21.
4. Becker W, Rapp W, Schwick HG, Störiko K. Methoden zur quantitativen Bestimmung von Plasmaproteinen durch Immunpräzipitation. Z Klin Chem 1968;6:113.
5. Billingham RE. The biology of graft-versus-host reactions. Harvey Lect 1966-67;62:21-78.
6. Cohen SB, Hurd ER. Neurological complications of connective tissue and other "collagen-vascular" diseases. Semin Arthritis Rheum 1981;11:190-212.
7. Eickhoff K, Heipertz R. Discrimination of elevated immunoglobulin concentrations in CSF due to inflammatory reaction of the central nervous system and blood-brain-barrier dysfunction. Acta Neurol Scand 1977;56:475-482.
8. Ferrara JLM, Deeg HJ. Graft-versus-host disease. N Engl J Med 1991 ¡324:667-674.
9. Fish man RA. Cerebrospinal fluid in diseases of the nervous system. Ed 2, Philadelphia:WB Saunders, 1992.
10. Fürst DE, Clements PJ, Graze P, Gale R, Roberts N. A syndrome resembling progressive systemic sclerosis after bone marrow transplantation: a model for scleroderma? Arth Rheum 1979;22:904-910.
11. Gottlieb M, Chavko M. Silver staining of native and denatured eucaryotic DNA in agarose gels. Analy Biochem 1987;165:33-37.
12. Graze PR, Gale RP. Chronic graft versus host disease: a syndrome of disordered immunity. Am J Med 1979,66:611-620.
13. Hickey WF. Microglial participation in the initiation of CNS inflammation. Disc Neurose 1993;9:74-78.
14. Hickey WF, Kimura H. Graft vs. host disease elicits expression of class I and class II histocompatibility antigens and the presence of scattered T lymphocytes in rat central nervous system. Proc Natl Acad Sci USA 1987;84:2082-2086.
15. Iwasaki Y, Sako K, Ohara Y, Miyazawa M, Minegishi M, Tsuchiya S, Konno T. Sub acute pan encephalitis associated with chronic graft-versus-host disease. Acta Neuropathol 1993;85:566-572.
16. Kajiwara K, Hirozane A, Fukumoto T, Orita T, Nishizaki T, Kamiryo T, Ito H. Major histocompatibility complex expression in brain of rats with graft-versus-host disease. J Neuroimmunol 1991;32:191-198.
17. Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 1970,227:680-685.
18. Lawley TJ, Peck GL, Moutsopoulos HM, Gratwohl AA, Deisseroth AB. Scleroderma, Sjögren-like syndrome, and chronic graft-versus-host disease. Ann Intern Med 1977;87:707-709.
19. Link H, Tibbling G. Principles of albumin and IgG analyses in neurological disorders: II. Relation of the concentration of the proteins in serum and cerebrospinal fluid. Scand J Clin Lab Invest 1977;37:391-396.
20. Livramento JA. Imunoglobilinas do liquido cefalorraqueano normal: II. Relações e indices. Arq Neuropsiquiat 1979;37:397-404.
21. Marosi C, Budka H, Grimm G, Zeitlhofer J, Sluga E, Brunner C, Schneeweiss B, Vole B, Bettelheim P, Panzer S, Kier P, Graninger W, Haas OA, Hinterberger W. Fatal encephalitis in a patient with chronic graft-versus-host disease. Bone Marrow Transpl 1990;6:53-57.
22. Mathé G, Amiel JL, Schwarzenberg L, Cattan A, Schneider M. Haematopoietic chimera in man after allogenic (homologous) bone-marrow transplantation:control of the secondary syndrome. Specific tolerance due to the chimerism. Br Med J 1963;28:1633-1635.
23. McLean BN, Luxton RW, Thompson EJ. A study of immunoglobulin G in the cerebro-spinal fluid of 1007 patients with suspected neurological disease using isoelectric focusing and the log Ig G- index. Brain 1990;113:1269-1289.
24. Morris A, Hewitt C, Young S. Control of the expression of genes for histocompatibility antigens. (The major histocompatibility complexes genes and their roles in antigen presentation). Molec Aspects Med 1994;15:411-423.
25. Openshaw H, Slatkin NE. Neurological complications of bone marrow transplantation. In Forman SJ, Blume KG, Thomas ED (ed). Bone marrow transplantation. Boston: Blackwell, 1994:482-96.
26. Parkman R. Clonal analysis of murine graft-vs-host diseased. Phenotypic and functional analysis of T lymphocyte clones. J Immunol 1986;136:3543-3547.
27. Patchell R A, White III CL, Clark AW, Beschorner WE, Santos GW. Neurologic complications of bone marrow transplantation. Neurology 1985;35:300-306.
28. Reiber H, Felgenhauer K. Protein transfer at the blood cerebrospinal fluid barrier and the quantitation of the humoral immune response within the central nervous system. Clin Chim Acta 1987;163:319-328.
29. Rouah E, Gruber R, Shearer W, Armstrong D, Hawkins EP. Graft-versus-host disease in central nervous system:a real entity? Am J Clin Pathol 1988;89:543-546.
30. Santos GW. History of bone marrow transplantation. Clin Haematol 1983; 12:611-639.
31. Schuller E, Sagar HJ. Local synthesis of CSF immunoglobulins:a neuroimmunological classification. J Neurol Sci 1981;51:361-370.
32. Sharief MK, Thompson EJ. Intrathecal immunoglobulin M synthesis in multiple sclerosis:relationship with clinical and cerebrospinal fluid parameters. Brain 1991;114:181-195.
33. Shulman HM, Sullivan KM, Weiden PL, McDonald GB, Striker GE, Sale GE, Hackman R, Tsoi M, Storb R, Thomas ED. Chronic graft-versus-host syndrome in man:a long-term clinicopathologic study of 20 Seattle patients. Am J Med 1980;69:204-217.
34. Sindic CJM, Cambiaso CL, Depré A, Laterre EC, Masson PL. The concentration of IgM in the cerebrospinal fluid of neurological patients. J Neurol Sci 1982;55:339-350.
35. Sullivan KM. Graft-versus-host disease. In Forman SJ, Blume KG, Thomas ED (eds). Bone marrow transplantation. Boston: Blackwell, 1994:339-362.
36. Thompson EJ. The CSF proteins: a biochemical approach. Amsterdam:Elsevier, 1988.
37. Tibbling G, Link H, Öhman S. Principles of albumin and IgG analyses in neurological disorders. I. Establishment of reference values. Scand J Clin Lab Invest 1977;37:385-390.
38. Tourtellotte WW. On cerebrospinal fluid immunoglobulin-G (IgG) quotients in multiple sclerosis and other diseases:a review and a new formula to estimate the amount of IgG synthesized per day by the central nervous system. J Neurol Sci 1970;10:279-304.
39. Van Bekkum DW. What is graft versus host disease? Bone Marrow Transpl 1991;7(Suppl 2): 110-111.
40. Wiznitzer M, Packer RJ, August CS, Burkey ED. Neurological complications of bone marrow transplantation in childhood. Ann Neurol 1984;16:569-576.

Datas de Publicação

Publicação nesta coleção
07 Out 2010
Data do Fascículo
1997

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

[1] 1. Anderton B, Thorpe RC. New methods of analyzing for antigens and glycoproteins in complex mixtures. Immunol Today 1980;1:122-127.

[2] 2. Barker CF, Billingham RE. Immunologically privileged sites. Adv Immunol 1977;25:1-8.

[3] 3. Barrett AJ. Graft versus host diseasexlinical features and biology. Bone Marrow Transpl 1989;4(Suppl 4): 18-21.

[4] 4. Becker W, Rapp W, Schwick HG, Störiko K. Methoden zur quantitativen Bestimmung von Plasmaproteinen durch Immunpräzipitation. Z Klin Chem 1968;6:113.

[5] 5. Billingham RE. The biology of graft-versus-host reactions. Harvey Lect 1966-67;62:21-78.

[6] 6. Cohen SB, Hurd ER. Neurological complications of connective tissue and other "collagen-vascular" diseases. Semin Arthritis Rheum 1981;11:190-212.

[7] 7. Eickhoff K, Heipertz R. Discrimination of elevated immunoglobulin concentrations in CSF due to inflammatory reaction of the central nervous system and blood-brain-barrier dysfunction. Acta Neurol Scand 1977;56:475-482.

[8] 8. Ferrara JLM, Deeg HJ. Graft-versus-host disease. N Engl J Med 1991 ¡324:667-674.

[9] 9. Fish man RA. Cerebrospinal fluid in diseases of the nervous system. Ed 2, Philadelphia:WB Saunders, 1992.

[10] 10. Fürst DE, Clements PJ, Graze P, Gale R, Roberts N. A syndrome resembling progressive systemic sclerosis after bone marrow transplantation: a model for scleroderma? Arth Rheum 1979;22:904-910.

[11] 11. Gottlieb M, Chavko M. Silver staining of native and denatured eucaryotic DNA in agarose gels. Analy Biochem 1987;165:33-37.

[12] 12. Graze PR, Gale RP. Chronic graft versus host disease: a syndrome of disordered immunity. Am J Med 1979,66:611-620.

[13] 13. Hickey WF. Microglial participation in the initiation of CNS inflammation. Disc Neurose 1993;9:74-78.

[14] 14. Hickey WF, Kimura H. Graft vs. host disease elicits expression of class I and class II histocompatibility antigens and the presence of scattered T lymphocytes in rat central nervous system. Proc Natl Acad Sci USA 1987;84:2082-2086.

[15] 15. Iwasaki Y, Sako K, Ohara Y, Miyazawa M, Minegishi M, Tsuchiya S, Konno T. Sub acute pan encephalitis associated with chronic graft-versus-host disease. Acta Neuropathol 1993;85:566-572.

[16] 16. Kajiwara K, Hirozane A, Fukumoto T, Orita T, Nishizaki T, Kamiryo T, Ito H. Major histocompatibility complex expression in brain of rats with graft-versus-host disease. J Neuroimmunol 1991;32:191-198.

[17] 17. Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 1970,227:680-685.

[18] 18. Lawley TJ, Peck GL, Moutsopoulos HM, Gratwohl AA, Deisseroth AB. Scleroderma, Sjögren-like syndrome, and chronic graft-versus-host disease. Ann Intern Med 1977;87:707-709.

[19] 19. Link H, Tibbling G. Principles of albumin and IgG analyses in neurological disorders: II. Relation of the concentration of the proteins in serum and cerebrospinal fluid. Scand J Clin Lab Invest 1977;37:391-396.

[20] 20. Livramento JA. Imunoglobilinas do liquido cefalorraqueano normal: II. Relações e indices. Arq Neuropsiquiat 1979;37:397-404.

[21] 21. Marosi C, Budka H, Grimm G, Zeitlhofer J, Sluga E, Brunner C, Schneeweiss B, Vole B, Bettelheim P, Panzer S, Kier P, Graninger W, Haas OA, Hinterberger W. Fatal encephalitis in a patient with chronic graft-versus-host disease. Bone Marrow Transpl 1990;6:53-57.

[22] 22. Mathé G, Amiel JL, Schwarzenberg L, Cattan A, Schneider M. Haematopoietic chimera in man after allogenic (homologous) bone-marrow transplantation:control of the secondary syndrome. Specific tolerance due to the chimerism. Br Med J 1963;28:1633-1635.

[23] 23. McLean BN, Luxton RW, Thompson EJ. A study of immunoglobulin G in the cerebro-spinal fluid of 1007 patients with suspected neurological disease using isoelectric focusing and the log Ig G- index. Brain 1990;113:1269-1289.

[24] 24. Morris A, Hewitt C, Young S. Control of the expression of genes for histocompatibility antigens. (The major histocompatibility complexes genes and their roles in antigen presentation). Molec Aspects Med 1994;15:411-423.

[25] 25. Openshaw H, Slatkin NE. Neurological complications of bone marrow transplantation. In Forman SJ, Blume KG, Thomas ED (ed). Bone marrow transplantation. Boston: Blackwell, 1994:482-96.

[26] 26. Parkman R. Clonal analysis of murine graft-vs-host diseased. Phenotypic and functional analysis of T lymphocyte clones. J Immunol 1986;136:3543-3547.

[27] 27. Patchell R A, White III CL, Clark AW, Beschorner WE, Santos GW. Neurologic complications of bone marrow transplantation. Neurology 1985;35:300-306.

[28] 28. Reiber H, Felgenhauer K. Protein transfer at the blood cerebrospinal fluid barrier and the quantitation of the humoral immune response within the central nervous system. Clin Chim Acta 1987;163:319-328.

[29] 29. Rouah E, Gruber R, Shearer W, Armstrong D, Hawkins EP. Graft-versus-host disease in central nervous system:a real entity? Am J Clin Pathol 1988;89:543-546.

[30] 30. Santos GW. History of bone marrow transplantation. Clin Haematol 1983; 12:611-639.

[31] 31. Schuller E, Sagar HJ. Local synthesis of CSF immunoglobulins:a neuroimmunological classification. J Neurol Sci 1981;51:361-370.

[32] 32. Sharief MK, Thompson EJ. Intrathecal immunoglobulin M synthesis in multiple sclerosis:relationship with clinical and cerebrospinal fluid parameters. Brain 1991;114:181-195.

[33] 33. Shulman HM, Sullivan KM, Weiden PL, McDonald GB, Striker GE, Sale GE, Hackman R, Tsoi M, Storb R, Thomas ED. Chronic graft-versus-host syndrome in man:a long-term clinicopathologic study of 20 Seattle patients. Am J Med 1980;69:204-217.

[34] 34. Sindic CJM, Cambiaso CL, Depré A, Laterre EC, Masson PL. The concentration of IgM in the cerebrospinal fluid of neurological patients. J Neurol Sci 1982;55:339-350.

[35] 35. Sullivan KM. Graft-versus-host disease. In Forman SJ, Blume KG, Thomas ED (eds). Bone marrow transplantation. Boston: Blackwell, 1994:339-362.

[36] 36. Thompson EJ. The CSF proteins: a biochemical approach. Amsterdam:Elsevier, 1988.

[37] 37. Tibbling G, Link H, Öhman S. Principles of albumin and IgG analyses in neurological disorders. I. Establishment of reference values. Scand J Clin Lab Invest 1977;37:385-390.

[38] 38. Tourtellotte WW. On cerebrospinal fluid immunoglobulin-G (IgG) quotients in multiple sclerosis and other diseases:a review and a new formula to estimate the amount of IgG synthesized per day by the central nervous system. J Neurol Sci 1970;10:279-304.

[39] 39. Van Bekkum DW. What is graft versus host disease? Bone Marrow Transpl 1991;7(Suppl 2): 110-111.

[40] 40. Wiznitzer M, Packer RJ, August CS, Burkey ED. Neurological complications of bone marrow transplantation in childhood. Ann Neurol 1984;16:569-576.